Carpal tunnel syndrome (CTS) is the most common compression neuropathy and has an immense impact on national health care, worker productivity, and quality of life. Despite its high prevalence and public health cost, our understanding of CTS is limited, and the management of CTS awaits improvement. Currently, CTS is routinely treated by carpal tunnel release surgery, which unfortunately has a number of complications. The concept of this surgical procedure has existed for nearly a century without fundamental challenges. Attempts have been made to conservatively treat CTS using manual therapies, but their effectiveness is ambiguous due to the lack of scientific and clinical evidence In our pursuit of CTS management, we have serendipitously discovered a novel mechanism of carpal tunnel manipulation to obtain tunnel enlargement by narrowing the carpal arch width. This discovery has exciting potential for the development of conservative treatment strategies for CTS. Our approach to carpal tunnel manipulation is in sharp contrast to the existing controversial techniques that try to stretch the carpal arch outwards. Therefore, our ultimate goal is to develop a biomechanical treatment for CTS through rigorous scientific studies on the mechanics and pathomechanics of the carpal tunnel. Our central notion is that CTS can be treated by non-surgical, biomechanical manipulation of the carpal tunnel through the narrowing of the carpal arch width. We hypothesize that strategically applied compression on the wrist can increase carpal tunnel cross-sectional area and decrease carpal tunnel pressure, thus relieving the median nerve from mechanical insult. We will test this hypothesis by systematically investigating the biomechanical relationships among transverse compressive force, carpal tunnel pressure, carpal arch width, and carpal tunnel cross-sectional area using cadaveric specimens and human subjects. The implementation of this project will yield novel knowledge on carpal tunnel mechanics and pathomechanics, leading to an evidence-based, novel biomechanical treatment strategy for CTS. PUBLIC HEALTH RELEVANCE: Carpal tunnel syndrome (CTS) is a well-known hand disorder and has an immense impact on health care, worker productivity, and quality of life. Annually, about half a million Americans undergo carpal tunnel surgery to cut the transverse carpal ligament to relieve the symptoms of CTS. Undoubtedly, the ligament exists to serve important anatomical, biomechanical and physiological functions; thus it should be preserved rather than cut. There is a long history of utilizing manual therapies for non-surgical treatment of CTS; however, the effectiveness of these interventions remains ambiguous due to the absence of convincing scientific and clinical evidence. We have discovered a novel mechanism to enlarge the carpal tunnel through biomechanical manipulation. This discovery has exciting potential for the development of a conservative treatment for CTS. Therefore, our project will ultimately develop a non-invasive biomechanical treatment of CTS through rigorous scientific investigation into the mechanics and pathomechanics of the carpal tunnel using cadaveric specimens and human subjects.